Frontiers in Cell and Developmental Biology | Mitochondrial Research section | New and Recent Articleshttps://www.frontiersin.org/journals/cell-and-developmental-biology/sections/mitochondrial-research
RSS Feed for Mitochondrial Research section in the Frontiers in Cell and Developmental Biology journal | New and Recent Articlesen-usFrontiers Feed Generator,version:12019-09-15T10:06:14.7581976+00:0060https://www.frontiersin.org/articles/10.3389/fcell.2019.00154https://www.frontiersin.org/articles/10.3389/fcell.2019.00154
What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion?2019-08-07T00:00:00ZBenedict C. AlbensiA large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function. However, studies on NF-κB activity in mitochondrial function are much more limited and scattered throughout the literature. For example, in 2001 it was first published that NF-κB subunits were found in the mitochondria, including not only IkBα and NF-κB p65 subunits, but also NF-κB pathway proteins such as IKKα, IKKβ, and IKKγ, but not much follow-up work has been done to date. Upon further thought the lack of studies on NF-κB activity in mitochondrial function is surprising given the importance and the evolutionary history of both NF-κB and the mitochondrion. Both are ancient in their appearance in our biological record where both contribute substantially to cell survival, cell death, and the regulation of function and/or disease. Studies also show NF-κB can influence mitochondrial function from outside the mitochondria. Therefore, it is essential to understand the complexity of these roles both inside and out of this organelle. In this review, an attempt is made to understand how NF-κB activity contributes to overall mitochondrial function – both inside and out. The discussion at times is speculative and perhaps even provocative to some, since NF-κB does not yet have defined mitochondrial targeting sequences for some nuclear-encoded mitochondrial genes and mechanisms of mitochondrial import for NF-κB are not yet entirely understood. Also, the data associated with the mitochondrial localization of proteins must be yet further proved with additional experiments.]]>https://www.frontiersin.org/articles/10.3389/fcell.2019.00054https://www.frontiersin.org/articles/10.3389/fcell.2019.00054
Editorial: Mitochondrial Communication in Physiology, Disease and Aging2019-04-11T00:00:00ZNuno RaimundoAnita Kriskohttps://www.frontiersin.org/articles/10.3389/fcell.2019.00003https://www.frontiersin.org/articles/10.3389/fcell.2019.00003
Emerging Roles in the Biogenesis of Cytochrome c Oxidase for Members of the Mitochondrial Carrier Family2019-01-31T00:00:00ZOluwaseun B. OgunbonaSteven M. ClaypoolThe mitochondrial carrier family (MCF) is a group of transport proteins that are mostly localized to the inner mitochondrial membrane where they facilitate the movement of various solutes across the membrane. Although these carriers represent potential targets for therapeutic application and are repeatedly associated with human disease, research on the MCF has not progressed commensurate to their physiologic and pathophysiologic importance. Many of the 53 MCF members in humans are orphans and lack known transport substrates. Even for the relatively well-studied members of this family, such as the ADP/ATP carrier and the uncoupling protein, there exist fundamental gaps in our understanding of their biological roles including a clear rationale for the existence of multiple isoforms. Here, we briefly review this important family of mitochondrial carriers, provide a few salient examples of their diverse metabolic roles and disease associations, and then focus on an emerging link between several distinct MCF members, including the ADP/ATP carrier, and cytochrome c oxidase biogenesis. As the ADP/ATP carrier is regarded as the paradigm of the entire MCF, its newly established role in regulating translation of the mitochondrial genome highlights that we still have a lot to learn about these metabolite transporters.]]>https://www.frontiersin.org/articles/10.3389/fcell.2018.00103https://www.frontiersin.org/articles/10.3389/fcell.2018.00103
Validating the RedMIT/GFP-LC3 Mouse Model by Studying Mitophagy in Autosomal Dominant Optic Atrophy Due to the OPA1Q285STOP Mutation2018-09-19T00:00:00ZAlan DiotThomas AgnewJeremy SandersonChunyan LiaoJanet CarverRicardo Pires das NevesRajeev GuptaYanping GuoCaroline WatersSharon SetoMatthew J. DanielsEszter DombiTiffany LodgeKarl MortenSuzannah A. WilliamsTariq EnverFrancisco J. IborraMarcela VotrubaJoanna PoultonBackground: Autosomal dominant optic atrophy (ADOA) is usually caused by mutations in the essential gene, OPA1. This encodes a ubiquitous protein involved in mitochondrial dynamics, hence tissue specificity is not understood. Dysregulated mitophagy (mitochondria recycling) is implicated in ADOA, being increased in OPA1 patient fibroblasts. Furthermore, autophagy may be increased in retinal ganglion cells (RGCs) of the OPA1Q285STOP mouse model.

Aims: We developed a mouse model for studying mitochondrial dynamics in order to investigate mitophagy in ADOA.

Methods: We crossed the OPA1Q285STOP mouse with our RedMIT/GFP-LC3 mouse, harboring red fluorescent mitochondria and green fluorescent autophagosomes. Colocalization between mitochondria and autophagosomes, the hallmark of mitophagy, was quantified in fluorescently labeled organelles in primary cell cultures, using two high throughput imaging methods Imagestream (Amnis) and IN Cell Analyzer 1000 (GE Healthcare Life Sciences). We studied colocalization between mitochondria and autophagosomes in fixed sections using confocal microscopy.

Results: We validated our imaging methods for RedMIT/GFP-LC3 mouse cells, showing that colocalization of red fluorescent mitochondria and green fluorescent autophagosomes is a useful indicator of mitophagy. We showed that colocalization increases when lysosomal processing is impaired. Further, colocalization of mitochondrial fragments and autophagosomes is increased in cultures from the OPA1Q285STOP/RedMIT/GFP-LC3 mice compared to RedMIT/GFP-LC3 control mouse cells that were wild type for OPA1. This was apparent in both mouse embryonic fibroblasts (MEFs) using IN Cell 1000 and in splenocytes using ImageStream imaging flow cytometer (Amnis). We confirmed that this represents increased mitophagic flux using lysosomal inhibitors. We also used microscopy to investigate the level of mitophagy in the retina from the OPA1Q285STOP/RedMIT/GFP-LC3 mice and the RedMIT/GFP-LC3 control mice. However, the expression levels of fluorescent proteins and the image signal-to-background ratios precluded the detection of colocalization so we were unable to show any difference in colocalization between these mice.

Conclusions: We show that colocalization of fluorescent mitochondria and autophagosomes in cell cultures, but not fixed tissues from the RedMIT/GFP-LC3, can be used to detect mitophagy. We used this model to confirm that mitophagy is increased in a mouse model of ADOA. It will be useful for cell based studies of diseases caused by impaired mitochondrial dynamics.

]]>https://www.frontiersin.org/articles/10.3389/fcell.2018.00031https://www.frontiersin.org/articles/10.3389/fcell.2018.00031
Sensing the Stress: A Role for the UPRmt and UPRam in the Quality Control of Mitochondria2018-03-28T00:00:00ZSylvie CallegariSven DennerleinMitochondria exist as compartmentalized units, surrounded by a selectively permeable double membrane. Within is contained the mitochondrial genome and protein synthesis machinery, required for the synthesis of OXPHOS components and ultimately, ATP production. Despite their physical barrier, mitochondria are tightly integrated into the cellular environment. A constant flow of information must be maintained to and from the mitochondria and the nucleus, to ensure mitochondria are amenable to cell metabolic requirements and also to feedback on their functional state. This review highlights the pathways by which mitochondrial stress is signaled to the nucleus, with a particular focus on the mitochondrial unfolded protein response (UPRmt) and the unfolded protein response activated by the mistargeting of proteins (UPRam). Although these pathways were originally discovered to alleviate proteotoxic stress from the accumulation of mitochondrial-targeted proteins that are misfolded or unimported, we review recent findings indicating that the UPRmt can also sense defects in mitochondrial translation. We further discuss the regulation of OXPHOS assembly and speculate on a possible role for mitochondrial stress pathways in sensing OXPHOS biogenesis.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00120https://www.frontiersin.org/articles/10.3389/fcell.2017.00120
Mitochondrial Tethers and Their Impact on Lifespan in Budding Yeast2018-01-08T00:00:00ZWolfgang M. PerniceTheresa C. SwayneIstvan R. BoldoghLiza A. PonTethers that link mitochondria to other organelles are critical for lipid and calcium transport as well as mitochondrial genome replication and fission of the organelle. Here, we review recent advances in the characterization of interorganellar mitochondrial tethers in the budding yeast, Saccharomyces cerevisiae. We specifically focus on evidence for a role for mitochondrial tethers that anchor mitochondria to specific regions within yeast cells. These tethering events contribute to two processes that are critical for normal replicative lifespan: inheritance of fitter mitochondria by daughter cells, and retention of a small pool of higher-functioning mitochondria in mother cells. Since asymmetric inheritance of mitochondria also occurs in human mammary stem-like cells, it is possible that mechanisms underlying mitochondrial segregation in yeast also operate in other cell types.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00107https://www.frontiersin.org/articles/10.3389/fcell.2017.00107
Protein Localization at Mitochondria-ER Contact Sites in Basal and Stress Conditions2017-12-12T00:00:00ZNicolò IlacquaMiguel Sánchez-ÁlvarezMagdalena BachmannVeronica CostinitiMiguel A. Del PozoMarta GiacomelloMitochondria-endoplasmic reticulum (ER) contacts (MERCs) are sites at which the outer mitochondria membrane and the Endoplasmic Reticulum surface run in parallel at a constant distance. The juxtaposition between these organelles determines several intracellular processes such as to name a few, Ca2+ and lipid homeostasis or autophagy. These specific tasks can be exploited thanks to the enrichment (or re-localization) of dedicated proteins at these interfaces. Recent proteomic studies highlight the tissue specific composition of MERCs, but the overall mechanisms that control MERCs plasticity remains unclear. Understanding how proteins are targeted at these sites seems pivotal to clarify such contextual function of MERCs. This review aims to summarize the current knowledge on protein localization at MERCs and the possible contribution of the mislocalization of MERCs components to human disorders.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00110https://www.frontiersin.org/articles/10.3389/fcell.2017.00110
Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease2017-12-12T00:00:00ZNicoletta PlotegherMichael R. DuchenParkinson's disease (PD) is the most common motor neurodegenerative disorder. In most cases the cause of the disease is unknown, while in about 10% of subjects, it is associated with mutations in a number of different genes. Several different mutations in 15 genes have been identified as causing familial forms of the disease, while many others have been identified as risk factors. A striking number of these genes are either involved in the regulation of mitochondrial function or of endo-lysosomal pathways. Mutations affecting one of these two pathways are often coupled with defects in the other pathway, suggesting a crosstalk between them. Moreover, PD-linked mutations in genes encoding proteins with other functions are frequently associated with defects in mitochondrial and/or autophagy/lysosomal function as a secondary effect. Even toxins that impair mitochondrial function and cause parkinsonian phenotypes, such as rotenone, also impair lysosomal function. In this review, we explore the reciprocal relationship between mitochondrial and lysosomal pathways in PD. We will discuss the impact of mitochondrial dysfunction on the lysosomal compartment and of endo-lysosomal defects on mitochondrial function, and explore the roles of both causative genes and genes that are risk factors for PD. Understanding the pathways that govern these interactions should help to define a framework to understand the roles and mechanisms of mitochondrial and lysosomal miscommunication in the pathophysiology of PD.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00106https://www.frontiersin.org/articles/10.3389/fcell.2017.00106
Mitochondria and Lysosomes: Discovering Bonds2017-12-07T00:00:00ZKiran TodkarHema S. IlamathiMarc GermainIn the last decade, the traditional view of lysosomes has been challenged by the recognition that lysosomes are not only degradative organelles, but also metabolic sensors that play a key role in the regulation of metabolism and cell growth. Similarly, mitochondria are now seen as crucial metabolic hubs dictating cell fate decisions, not just ATP-producing machines. Importantly, these functions are generally performed as a coordinate response of distinct organelles that are physically and functionally connected. While the association between mitochondria and the endoplasmic reticulum is well known, a similar interaction between mitochondria and lysosomes is now emerging. This interaction could be required to shuttle amino acids, lipids and ions such as Ca2+ between the two organelles, thereby modulating their metabolic functions. In addition, a tethering complex linking the two organelles has recently been described in yeast, although the mammalian counterpart has yet to be identified. Here, we discuss the implications of these recent findings.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00095https://www.frontiersin.org/articles/10.3389/fcell.2017.00095
Interorganelle Communication between Mitochondria and the Endolysosomal System2017-11-07T00:00:00ZGonzalo Soto-HerederoFrancesc BaixauliMaría MittelbrunnThe function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.]]>https://www.frontiersin.org/articles/10.3389/fcell.2017.00090https://www.frontiersin.org/articles/10.3389/fcell.2017.00090
Role of Cardiolipin in Mitochondrial Signaling Pathways2017-09-29T00:00:00ZJan DudekThe phospholipid cardiolipin (CL) is an essential constituent of mitochondrial membranes and plays a role in many mitochondrial processes, including respiration and energy conversion. Pathological changes in CL amount or species composition can have deleterious consequences for mitochondrial function and trigger the production of reactive oxygen species. Signaling networks monitor mitochondrial function and trigger an adequate cellular response. Here, we summarize the role of CL in cellular signaling pathways and focus on tissues with high-energy demand, like the heart. CL itself was recently identified as a precursor for the formation of lipid mediators. We highlight the concept of CL as a signaling platform. CL is exposed to the outer mitochondrial membrane upon mitochondrial stress and CL domains serve as a binding site in many cellular signaling events. During mitophagy, CL interacts with essential players of mitophagy like Beclin 1 and recruits the autophagic machinery by its interaction with LC3. Apoptotic signaling pathways require CL as a binding platform to recruit apoptotic factors such as tBid, Bax, caspase-8. CL required for the activation of the inflammasome and plays a role in inflammatory signaling. As changes in CL species composition has been observed in many diseases, the signaling pathways described here may play a general role in pathology.]]>https://www.frontiersin.org/articles/10.3389/fcell.2016.00145https://www.frontiersin.org/articles/10.3389/fcell.2016.00145
Editorial: Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation2016-12-21T00:00:00ZMichael SchraderMarkus Islingerhttps://www.frontiersin.org/articles/10.3389/fcell.2016.00022https://www.frontiersin.org/articles/10.3389/fcell.2016.00022
Using Optical Tweezers to Characterize Physical Tethers at Membrane Contact Sites: Grab It, Pull It, Set It Free?2016-03-29T00:00:00ZImogen Sparkeshttps://www.frontiersin.org/articles/10.3389/fcell.2016.00019https://www.frontiersin.org/articles/10.3389/fcell.2016.00019
Microtubules Are Essential for Mitochondrial Dynamics–Fission, Fusion, and Motility–in Dictyostelium discoideum2016-03-22T00:00:00ZLaken C. WoodsGregory W. BerbusseKari NaylorMitochondrial function is dependent upon mitochondrial structure which is in turn dependent upon mitochondrial dynamics, including fission, fusion, and motility. Here we examined the relationship between mitochondrial dynamics and the cytoskeleton in Dictyostelium discoideum. Using time-lapse analysis, we quantified mitochondrial fission, fusion, and motility in the presence of cytoskeleton disrupting pharmaceuticals and the absence of the potential mitochondria-cytoskeleton linker protein, CluA. Our results indicate that microtubules are essential for mitochondrial movement, as well as fission and fusion; actin plays a less significant role, perhaps selecting the mitochondria for transport. We also suggest that CluA is not a linker protein but plays an unidentified role in mitochondrial fission and fusion. The significance of our work is to gain further insight into the role the cytoskeleton plays in mitochondrial dynamics and function. By better understanding these processes we can better appreciate the underlying mitochondrial contributions to many neurological disorders characterized by altered mitochondrial dynamics, structure, and/or function.]]>https://www.frontiersin.org/articles/10.3389/fcell.2016.00006https://www.frontiersin.org/articles/10.3389/fcell.2016.00006
High Light Intensity Leads to Increased Peroxule-Mitochondria Interactions in Plants2016-02-04T00:00:00ZErica-Ashley JaipargasNeeta MathurFiras Bou DaherGeoffrey O. WasteneysJaideep MathurPeroxules are thin protrusions from spherical peroxisomes produced under low levels of reactive oxygen species (ROS) stress. Whereas, stress mitigation favors peroxule retraction, prolongation of the ROS stress leads to the elongation of the peroxisome into a tubular form. Subsequently, the elongated form becomes constricted through the binding of proteins such as dynamin related proteins 3A and 3B and eventually undergoes fission to increase the peroxisomal population within a cell. The events that occur in the short time window between peroxule initiation and the tubulation of the entire peroxisome have not been observed in living plant cells. Here, using fluorescent protein aided live-imaging, we show that peroxules are formed after only 4 min of high light (HL) irradiation during which there is a perceptible increase in the cytosolic levels of hydrogen peroxide. Using a stable, double transgenic line of Arabidopsis thaliana expressing a peroxisome targeted YFP and a mitochondrial targeted GFP probe, we observed sustained interactions between peroxules and small, spherical mitochondria. Further, it was observed that the frequency of HL-induced interactions between peroxules and mitochondria increased in the Arabidopsis anisotropy1 mutant that has reduced cell wall crystallinity and where we show accumulation of higher H2O2 levels than wild type plants. Our observations suggest a testable model whereby peroxules act as interaction platforms for ROS-distressed mitochondria that may release membrane proteins and fission factors. These proteins might thus become easily available to peroxisomes and facilitate their proliferation for enhancing the ROS-combating capability of a plant cell.]]>https://www.frontiersin.org/articles/10.3389/fcell.2015.00083https://www.frontiersin.org/articles/10.3389/fcell.2015.00083
Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum2016-01-28T00:00:00ZRonald J. A. WandersHans R. WaterhamSacha FerdinandussePeroxisomes are unique subcellular organelles which play an indispensable role in several key metabolic pathways which include: (1.) etherphospholipid biosynthesis; (2.) fatty acid beta-oxidation; (3.) bile acid synthesis; (4.) docosahexaenoic acid (DHA) synthesis; (5.) fatty acid alpha-oxidation; (6.) glyoxylate metabolism; (7.) amino acid degradation, and (8.) ROS/RNS metabolism. The importance of peroxisomes for human health and development is exemplified by the existence of a large number of inborn errors of peroxisome metabolism in which there is an impairment in one or more of the metabolic functions of peroxisomes. Although the clinical signs and symptoms of affected patients differ depending upon the enzyme which is deficient and the extent of the deficiency, the disorders involved are usually (very) severe diseases with neurological dysfunction and early death in many of them. With respect to the role of peroxisomes in metabolism it is clear that peroxisomes are dependent on the functional interplay with other subcellular organelles to sustain their role in metabolism. Indeed, whereas mitochondria can oxidize fatty acids all the way to CO2 and H2O, peroxisomes are only able to chain-shorten fatty acids and the end products of peroxisomal beta-oxidation need to be shuttled to mitochondria for full oxidation to CO2 and H2O. Furthermore, NADH is generated during beta-oxidation in peroxisomes and beta-oxidation can only continue if peroxisomes are equipped with a mechanism to reoxidize NADH back to NAD+, which is now known to be mediated by specific NAD(H)-redox shuttles. In this paper we describe the current state of knowledge about the functional interplay between peroxisomes and other subcellular compartments notably the mitochondria and endoplasmic reticulum for each of the metabolic pathways in which peroxisomes are involved.]]>https://www.frontiersin.org/articles/10.3389/fcell.2015.00078https://www.frontiersin.org/articles/10.3389/fcell.2015.00078
Mitochondrial Dynamics and the ER: The Plant Perspective2015-12-23T00:00:00ZStefanie J. MuellerRalf ReskiWhereas contact sites between mitochondria and the ER have been in the focus of animal and fungal research for several years, the importance of this organellar interface and the molecular effectors are largely unknown for plants. This work gives an introduction into known evolutionary differences of molecular effectors of mitochondrial dynamics and interactions between animals, fungi, and plants. Using the model plant Physcomitrella patens, we provide microscopic evidence for the existence of mitochondria-ER interactions in plants and their correlation with mitochondrial constriction and fission. We further investigate a previously identified protein of unknown function (MELL1), and show that it modulates the amount of mitochondrial association to the ER, as well as mitochondrial shape and number.]]>https://www.frontiersin.org/articles/10.3389/fcell.2015.00056https://www.frontiersin.org/articles/10.3389/fcell.2015.00056
The different facets of organelle interplay—an overview of organelle interactions2015-09-25T00:00:00ZMarkus IslingerLuis Felipe GodinhoJoseph CostelloMichael SchraderMembrane-bound organelles such as mitochondria, peroxisomes, or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown, or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signaling, cellular maintenance, cell fate decision, and pathogen defence. In order to facilitate such signaling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signaling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes, and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so-called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy—a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signaling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction.]]>https://www.frontiersin.org/articles/10.3389/fcell.2015.00049https://www.frontiersin.org/articles/10.3389/fcell.2015.00049
The lipid droplet—a well-connected organelle2015-08-12T00:00:00ZQiang GaoJoel M GoodmanOur knowledge of inter-organellar communication has grown exponentially in recent years. This review focuses on the interactions that cytoplasmic lipid droplets have with other organelles. Twenty-five years ago droplets were considered simply particles of coalesced fat. Ten years ago there were hints from proteomics studies that droplets might interact with other structures to share lipids and proteins. Now it is clear that the droplets interact with many if not most cellular structures to maintain cellular homeostasis and to buffer against insults such as starvation. The evidence for this statement, as well as probes to understand the nature and results of droplet interactions, are presented.]]>https://www.frontiersin.org/articles/10.3389/fcell.2015.00042https://www.frontiersin.org/articles/10.3389/fcell.2015.00042
Hypoxia signaling pathways: modulators of oxygen-related organelles2015-07-21T09:27:19ZMiriam Johanna SchönenbergerWerner Josef KovacsOxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health.]]>